rs61734621

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000069.3(CACNA1S):​c.858C>T​(p.Tyr286=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00373 in 1,614,250 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 51 hom., cov: 32)
Exomes 𝑓: 0.0025 ( 53 hom. )

Consequence

CACNA1S
NM_000069.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.896
Variant links:
Genes affected
CACNA1S (HGNC:1397): (calcium voltage-gated channel subunit alpha1 S) This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BP6
Variant 1-201089300-G-A is Benign according to our data. Variant chr1-201089300-G-A is described in ClinVar as [Benign]. Clinvar id is 254854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.896 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0153 (2337/152360) while in subpopulation AFR AF= 0.0487 (2027/41582). AF 95% confidence interval is 0.047. There are 51 homozygotes in gnomad4. There are 1098 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 51 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1SNM_000069.3 linkuse as main transcriptc.858C>T p.Tyr286= synonymous_variant 6/44 ENST00000362061.4 NP_000060.2
CACNA1SXM_005245478.4 linkuse as main transcriptc.858C>T p.Tyr286= synonymous_variant 6/43 XP_005245535.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1SENST00000362061.4 linkuse as main transcriptc.858C>T p.Tyr286= synonymous_variant 6/441 NM_000069.3 ENSP00000355192 P2

Frequencies

GnomAD3 genomes
AF:
0.0153
AC:
2327
AN:
152242
Hom.:
50
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0486
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00844
Gnomad ASJ
AF:
0.0196
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00118
Gnomad OTH
AF:
0.0143
GnomAD3 exomes
AF:
0.00534
AC:
1343
AN:
251416
Hom.:
26
AF XY:
0.00419
AC XY:
570
AN XY:
135900
show subpopulations
Gnomad AFR exome
AF:
0.0524
Gnomad AMR exome
AF:
0.00416
Gnomad ASJ exome
AF:
0.0172
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000294
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.00120
Gnomad OTH exome
AF:
0.00440
GnomAD4 exome
AF:
0.00252
AC:
3690
AN:
1461890
Hom.:
53
Cov.:
33
AF XY:
0.00230
AC XY:
1674
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0519
Gnomad4 AMR exome
AF:
0.00499
Gnomad4 ASJ exome
AF:
0.0177
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000185
Gnomad4 FIN exome
AF:
0.000187
Gnomad4 NFE exome
AF:
0.000710
Gnomad4 OTH exome
AF:
0.00628
GnomAD4 genome
AF:
0.0153
AC:
2337
AN:
152360
Hom.:
51
Cov.:
32
AF XY:
0.0147
AC XY:
1098
AN XY:
74504
show subpopulations
Gnomad4 AFR
AF:
0.0487
Gnomad4 AMR
AF:
0.00843
Gnomad4 ASJ
AF:
0.0196
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.00118
Gnomad4 OTH
AF:
0.0142
Alfa
AF:
0.00957
Hom.:
19
Bravo
AF:
0.0179
Asia WGS
AF:
0.00375
AC:
13
AN:
3478
EpiCase
AF:
0.00169
EpiControl
AF:
0.00190

ClinVar

Significance: Benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsAug 03, 2018- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 06, 2023- -
Malignant hyperthermia, susceptibility to, 5 Benign:3
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthAug 17, 2022- -
Benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthFeb 05, 2024- -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxAug 31, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Hypokalemic periodic paralysis, type 1 Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Malignant hyperthermia, susceptibility to, 5;C2749982:Thyrotoxic periodic paralysis, susceptibility to, 1;C3714580:Hypokalemic periodic paralysis, type 1 Benign:1
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 14, 2022- -
Congenital myopathy 18 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Thyrotoxic periodic paralysis, susceptibility to, 1 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.48
CADD
Benign
7.9
DANN
Benign
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61734621; hg19: chr1-201058428; API